Potassium Carbonate → 3-(3,4-Dihydro-2H-benzo[b] [1,4]dioxepin-7-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo [1,2-b]pyrazole

HRID 751301Notes

Reaction equation

HRID 751301 reaction equation
Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:5][N:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[O:16]1[CH2:22][CH2:21][CH2:20][O:19][C:18]2[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:17]1=2.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:16]1[CH2:22][CH2:21][CH2:20][O:19][C:18]2[CH:23]=[C:24]([C:2]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][N:4]4[CH2:13][CH2:14][CH2:15][C:3]=34)[CH:25]=[CH:26][C:17]1=2

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 27763983,4-Dihydro-2H-1,5-benzodioxepin-7-ylboronic acidHCID 597100253-bromo-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Product 1

HCID 103369193-(3,4-Dihydro-2H-benzo[b] [1,4]dioxepin-7-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo [1,2-b]pyrazoleYield 22%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

Add bis(1,2-bis(diphenylphosphino)ethane)palladium(0) (Pd(DIPHOS)2; 0.086 g, 0.095 mmol) and tris(dibenzylidene-acetone)dipalladium(0) (Pd2(dba)3); 0.088 g, 0.095 mmol) to a degassed solution of 3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Preparation 4, 0.25 g, 0.95 mmol) in THF (2.5 mL). Purge the reaction mixture with nitrogen for 2 min and stir for 20 min at room temperature. Add 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylboronic acid (158 mg, 0.95 mmol) in DMF (1 mL). After stirring the reaction mixture for 10 min, add 2M aqueous potassium carbonate solution (1.2 mL). Heat the solution at 65° C. for 1 h. Add Pd2(dba)3 (0.088 g, 0.095 mmol) twice after 1 h and again after 2 h. Continue stirring the reaction mixture for 15 h at 65° C. Cool the mixture to room temperature, filter through a Celite® pad, and wash the celite pad with dichloromethane (50 mL) and methanol (50 mL). Evaporate the filtrate. Purification of the residue by flash chromatography (SiO2, 1:3 [88:8:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane) gives the title compound (69 mg, 22%) as a brown oil.

Workup

  1. customPurge the reaction mixture with nitrogen for 2 min
  2. stirringAfter stirring the reaction mixture for 10 min
  3. temperatureHeat the solution at 65° C. for 1 h
  4. waitagain after 2 h
  5. stirringContinue stirring the reaction mixture for 15 h at 65° C
  6. temperatureCool the mixture to room temperature
  7. filtrationfilter through a Celite® pad
  8. washwash the celite pad with dichloromethane (50 mL) and methanol (50 mL)
  9. customEvaporate the filtrate
  10. customPurification of the residue by flash chromatography (SiO2, 1:3 [88:8:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane)

Sources & evidence

ORD record
ord-bc5ace708ac04080ac923eed2d47fa5b
Source dataset
uspto-grants-2008_07
Patent number
US07405299B2

Reaction notes

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